Project. 4. The long-range goal of this proposal is to determine if neurokinin-1 receptor (NK-1R) (substance P preferring) antagonists have anti HIV-1 activity in vivo. The short-range goal of this study is to determine the safety, viral suppressive potential, pharmacokinetics in HIV infected individuals and immune modulatory effects of treatment with aprepitant (Emend) Aprepitant is the only FDA approved substance P antagonist. This project is directly linked to the other 3 projects of this program project proposal and will define the potential utility of this new class of antiviral agents. Specific Aim 1: Examine the safety and tolerability of the NK-1R antagonist, aprepitant, in HIV-infected subjects during 4-weeks of therapy. Our hypothesis is that aprepitant will be safe, tolerable and have antiviral activity in HIV infected individuals. To test this hypothesis we will determine the antiviral activity of this compound by comparing the change in HIV RNA viral load of 27 individuals after 4 weeks of aprepitant administration as monotherapy in a randomized 1:1:1 placebo-controlled phase Ib trial in individuals with high CD4 cell counts that have not started antiretroviral therapy. Specific Aim 2: Determine aprepitant plasma concentrations over the 4 weeks of clinical evaluation in order to develop a population-based pharmacokinetic-pharmacodynamic (PK/PD) model for aprepitant in HIV-infected patients. Assess the exposure-response relationship to evaluate aprepitant's ability to suppress HIV-1 RNA. Specific Aim 3: To evaluate the potential immunoregulatory role of neurokinin-1 receptor (substance P preferring) antagonists in HIV infected individuals and their effects on CCR5 expression (aim 3a), NK cell function in vitro (aim 3b) and in vivo (aim 3c). Specific Aim 4: Evaluation of the link between neurokinin-1 receptor substance P antagonists, immune cell function and indices of psychological disturbance in exploratory investigations. Assessment depression, anxiety, and sleep quality relative to baseline before and after the administration of aprepitant.